1. Field of the Invention
The subject invention is generally directed to the long term storage of thymoxamine at room temperature and, more particularly, to the use of dimethyl-beta-cyclodextrin as a complexing agent to stabilize thymoxamine.
2. Description of the Prior Art
Thymoxamine is a competitive alpha-adrenoceptor blocking agent and has weak anti-histamine activity. The drug has been used in the clinical setting in Europe for causing vasodilation, decreasing blood pressure, and improving blood circulation in the brain. Thymoxamine has been found to reverse mydriasis (prolonged and abnormal dilation of the pupil of an eye) caused by epinephrine or ephredine. Thymoxamine is also commonly known as moxisylyte and has the following chemical formula: 4-[2-(dimethylamino)ethoxy]-2-methyl-5-(1-methylethyl)-phenol acetate. In its clinical applications, thymoxamine typically has a coordinated hydrochloride molecule.
FIG. 1 shows that thymoxamine is susceptible to both base and acid catalyzed degradation. The drug contains a phenol acetate moiety which is vulnerable to base catalyzed hydrolysis to a phenol and to acid catalyzed hydrolysis with subsequent oxidation to a quinone. The rate of hydrolysis of thymoxamine is pseudo-first-order and takes many days at pH levels between 2 and 7; however, at high pH levels, the rate of hydrolysis is on the order of minutes. The hydrolysis of thymoxamine gives a linear Arrhenius plot in water from 40.degree. to 60.degree. C.
Long term storage of the drug at room temperature has not been possible because of the hydrolysis problems. Giovanni, in J. of Ophthalmology, 105(3), 1988, page 32, has reported that solutions of thymoxamine are not stable at ambient temperature unless refrigerated. The formulation specifications for refrigerated thymoxamine require a pH range of 4.4 to 6.4; however, control of the pH in the formulation has not provided completely satisfactory results.
FIG. 2 shows the torroidal shape of a beta-cyclodextrin molecule. The primary hydroxyl groups project from one outer edge and the secondary hydroxyl groups project from the other. The result is a molecule with a hydrophobic center and a relatively hydrophilic outer surface. Beta-cyclodextrin's have been used to enhance the solubility and stability of drugs in aqueous solution. Passington, in Chemistry of Britain, May 1987, page 457, has reported that beta-cyclodextrin complexes or "inclusion compounds" enhance the solubility of prostoglandins, steroid hormones, diuretics, and barbiturates, stabilize the hydrolysis of aspirin, atropine, and procaine, stabilize the oxidation of chlorpromazine and epinephrine, stabilize the dehydration of prostaglandin E groups, and enhance the bio-availability of aspirin, phenytoin, and digoxin. In addition, beta-cyclodextrins prevent evaporation, improve the bad smell of various drugs, reduce stomach injury, and inhibit hemolysis. Studies have shown that benzocaine complexed with beta-cyclodextrin does not undergo alkaline hydrolysis while dissociated benzocaine does.
FIG. 3 shows complexation with betacyclodextrin is a reversible process. In aqueous solution, the guest molecule penetrates into the hydrophobic cavity forming a complex or "inclusion compound", and the exterior of the betacyclodextrin becomes hydrated. Dissociation of the beta-cyclodextrin complex is governed by the guest material. The stability of many beta-cyclodextrin complexes in aqueous solution can speed up or slow down a chemical reaction. For example, studies of aminobenzoic acids have revealed that when the reactive groups are within the beta-cyclodextrin cavity, the rate of hydrolysis decreases; however, if the active groups are outside the cavity the hydrolysis rate increases.
FIG. 4 shows heptakis-2,6-di-O-methyl-beta-cyclodextrin which is often abbreviated a dimethyl-beta-cyclodextrin (DMBCD). DMBCD is prepared by selective methylation of the C(2) and C(6) primary hydroxyls of beta-cyclodextrin while the C(3) hydroxyls remain unsubstituted. DMBCD has a torroidal shape similar to that shown in FIG. 2 and inclusion complexes are formed with DMBCD in a manner similar to that shown in FIG. 3.
Szejtli, in Journal of Inclusion Phenomena, 1, 1983, pages 135-150, examined the use of DMBCD as a parenteral drug carrier. DMBCD does not cause the renal toxicity that beta-cyclodextrin causes and is more soluble than beta-cyclodextrin. DMBCD was found to enhance the solubility of lidocaine, marcaine, vitamin D.sub.3 and vitamin K.sub.3 by forming an inclusion complex with those molecules. The diffusion rate of a parenterally administered drug complexed with DMBCD was slowed such that the time duration for which an anesthesia remained effective was extended. In addition, complexing vitamins with DMBCD decreased the level of free vitamin and thereby reduced vitamin toxicity.
No studies have discussed the possibility of complexing DMBCD with thymoxamine for the purpose of preventing hydrolysis. Before the invention thereof by the applicants, it was not known that thymoxamine could form an inclusion compound with DMBCD. Moreover, before the invention thereof by the applicants, it was not known that thymoxamine would be stabilized by formation of an inclusion complex, i.e., as noted above, inclusion complexes can sometimes speed up a chemical reaction rather than slow it down.